tbuckley/cabot-search huggingface dataset:
QOL-16. GLIOBLASTOMAS LOCATED IN THE RIGHT INFERIOR PARIETAL LOBE CAUSE A POOR POSTOPERATIVE PERFORMANCE LEVEL
Authors: Mitsutoshi Nakada, Riho Nakajima, Masashi Kinoshita
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Managing quality of life has become more important for patients with glioblastoma (GBM). Maintaining independence levels should be given attention while treating GBM. Postoperatively, non-dominant hemispheric GBMs often decrease the Karnofsky Performance Status (KPS) score. This study aimed to investigate the factors that lead to poor KPS scores after tumor resection in non-dominant hemispheric GBM. METHODS Forty-one patients newly diagnosed GBM in the right cerebral hemisphere who underwent resection were included. Brain functions were assessed preoperatively and postoperatively. First, the KPS scores before and after surgery were compared. Second, univariate and multiple regression analyses and voxel-based lesion-symptom mapping (VLSM) were performed to analyze the functions and brain regions related to KPS, respectively. Third, factors associated with prognosis were analyzed using the log-rank test. RESULTS Compared with the preoperative status, KPS significantly decreased after the surgery (81.0% vs. 73.6%, p = 0.020). Brain functions affecting KPS include general cognitive function, processing speed, attention, memory, visuospatial cognition, emotion recognition, and executive function. Among these, multiple regression analysis revealed visuospatial cognition and emotion recognition to be significantly influenced KPS in the chronic postoperative phase (p = 0.030 and 0.048, respectively). VLSM demonstrated that resection of the inferior parietal lobe caused a significant decline in KPS. Visuospatial cognition and emotion recognition were impaired with a higher probability (p = 0.035 and 0.048, respectively) in patients with tumors located in the inferior parietal lobe. In addition, lesions in the inferior parietal lobe were associated with shorter overall survival (p = 0.046). CONCLUSIONS GBMs in the right inferior parietal lobe are more likely to result in poor postoperative KPS due to impairment of visuospatial cognition and emotion recognition, which relate to a poor prognosis.
EXTH-60. OVERCOMING THE LEPTOMENINGEAL SEEDING OF MEDULLOBLASTOMA BY TARGETING HSP70
Authors: Seung Ah Choi, Saehim Ha, Seung-Ki Kim, Do Won Hwang, Sekhoeun Heung, Ji Hoon Phi
Journal: Neuro-Oncology (2023)

Abstract Purpose The development of leptomeningeal seeding (LMS) through the cerebrospinal fluid (CSF) is a common in medulloblastoma (MB) and a major cause of treatment failure. The mechanism of MB LMS remains unclear and effective treatment options are urgently required. This study aimed to discover molecules that can specifically target seeding cells by making a cellular model of MB LMS and analyzing their specific genetic and functional characteristics. METHODS: By repeated transplantation, separation, culture, seeding and non-seeding MB cells were isolated. The cellular characteristics of each group were compared and differentially expressed genes (DEGs) were determined through gene expression profiling. The therapeutic effect of the selected inhibitor on the selected protein was tested in vitro and in vivo. RESULTS: We separated seeding and non-seeding cells triply, with the DEGs analysis indicating that heat shock protein 70 (HSP70) was in the highest rank in the expression profile of the seeding cells, and pathway enrichment analysis revealed that the metabolism was the main pathway enriched in seeding cells. The proliferation of seeding cells (S3) was slower than that of non-seeding cells (N3), but there was no significant difference in viability. Notably, the wound-healing of S3 was delayed, but the adhesion ability on collagen was higher than N3. We tested the effect of HSP70 suppression. Among the six HSP70 inhibitors, VER155008 was efficiently sensitive to S3, and suppression of MRP proteins with HSP70 was observed. Importantly, the treatment of VER155008 reduced LMS along the spinal cord in vivo. In addition, a synergistic effect was observed in the combination treatment of VER155008 with 4-hydroperoxycyclophosphamide. CONCLUSION: Our study suggests that targeting HSP70 can be a promising treatment option to suppress the LMS of MB.
TMIC-09. PRIMARY CILIA REGULATE EXTRACELLULAR VESICLE-MEDIATED IMMUNOSUPPRESSION IN HUMAN GLIOBLASTOMA CELLS
Authors: Mi-Yeon Jung, Josie Trichka, Masahiro Oishi, Afua Agyeman-Andoh, Joshua Welsh, Jubin George, Amanda Roehrkasse, Maxwell Laws, Jennifer Jones, Stanley Adoro, Ian Parney, Desmond Brown
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma is the most common primary malignant brain tumor. Despite maximal safe resection, followed by chemoradiation, median survival is 15 months, and 5-year survival is 6.8%. Efficacy of immunotherapy is limited by glioblastoma-mediated immunosuppression. Extracellular vesicles (EVs) are a heterogeneous group of small membrane-bound particles that are released from all cell types. Glioblastoma-derived EVs regulate the tumor microenvironment and tumor progression in a paracrine manner. They also regulate glioblastoma-mediated systemic immunosuppression in an IL6- and PDL1-dependent manner by inducing myeloid-derived suppressor cells (MDSCs) ultimately resulting in T cell depletion. Primary cilia are ubiquitous microtubule-based organelles that project from the mother centriole and are present on glioblastoma cells. Inhibition of ciliogenesis–through knockdown of KIF3A, IFT88, or ARL13B (structural ciliary proteins required for ciliogenesis)–abolishes IL6 induction in response to chemoradiation and significantly reduces the induction of MDSCs in normal human donor monocytes exposed to glioblastoma-derived EVs. Inhibition of ciliogenesis does not affect the biophysical properties of EVs but our data instead suggest significant alterations in EV packaging and content in response to ciliary loss. These data suggest a novel role for primary cilia in packaging of EV contents and connects these organelles with tumor EV-mediated immunosuppression in glioblastomas. These findings have potential implications for improving the efficacy of immunotherapy in glioblastoma–a universally fatal disease.
CNSC-21. INVESTIGATING THE EVOLUTION OF NEURON-GLIOMA CIRCUIT DYNAMICS USING AN IN VIVO IMAGING METHOD
Authors: Kiarash Shamardani, Michael Keough, Michelle Monje
Journal: Neuro-Oncology (2023)

Abstract Pediatric high-grade gliomas (pHGG) are aggressive primary brain neoplasms with a dismal prognosis, making them the leading cause of brain tumor-related deaths in children. pHGGs occur in specific anatomical locations at specific ages underscoring their origin in neurodevelopment and the critical importance of the brain tumor microenvironment. Activity-regulated mechanisms are major regulators of neural development and plasticity. Many pHGGs originate from oligodendroglial precursor cells (OPC) and, like OPCs, neuronal activity promotes pHGG proliferation. Recent work has demonstrated that pHGG cells form calcium-permeable AMPAR-mediated synapses with neurons analogous to the axo-glial synapses that form between neurons and OPCs. Neuronal activity drives pHGG growth through secretion of activity-regulated mitogens and through electrochemical communication with pHGG cells that integrate into neural circuits. In turn, pHGG increases neuronal excitability and remodels functional neural circuits. The interconnected network of glioma cells and neurons is fundamental to pHGG progression. However, how these neuron-glioma networks evolve over time remains to be fully understood. We hypothesize that as gliomas progress, the neuron-glioma malignant circuitry evolves chiefly through synaptogenesis to promote activity that fosters glioma progression. Thus, we developed a two-color in vivo imaging method to study neuron-glioma cell interactions over time in freely behaving mice enabling us to record the frequency, pattern, and synchronicity of calcium transients in neurons, glioma cells, and their coactivity giving us a comprehensive view of the changes in neuron-glioma circuit dynamics over time. We have observed increasing neuronal activity throughout the disease, consistent with increasing neural hyperexcitability over time, and have observed that different types of gliomas exhibit unique patterns of calcium transients (rise time, peak amplitude, decay time, and half-width). Our imaging paradigm offers a unique ability to study neuron-glioma interactions at the systems level and will allow us to study how pharmacological inhibitors and neuronal experience shape neuron-glioma malignant circuit dynamics.
BIOM-48. A NOVEL LIQUID BIOPSY-BASED APPROACH TO ISOLATE AND CHARACTERIZE GLIOBLASTOMA-DERIVED SMALL EXTRACELLULAR VESICLES FROM BLOOD
Authors: Yangen He, Sameh Almousa, Ashish Kumar, Yixin Su, Mitu Sharma, Sangeeta Singh, Susy Kim, Glenn Lesser, Gagan Deep
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma multiforme (GBM) is a highly aggressive brain cancer characterized by a poor prognosis and limited treatment options. The absence of early diagnostic measures, prognostic biomarkers, and reliable methods for monitoring disease progression contribute to the high mortality rate among GBM patients. In recent years, liquid biopsy has emerged as a non-invasive tool for assessing cancer onset and therapeutic responses. Among the various liquid biopsy approaches, extracellular vesicles (EVs) have gained attention; as lipid bilayer membrane-delimited 30-150nm sized small extracellular vesicles (sEV) are released by all cell types. These vesicles carry molecular cargo reflecting the cell of origin and its pathophysiological state, making them a promising alternative to other liquid biopsy methods, such as circulating tumor cells and circulating nucleotides. However, the application of sEV-based liquid biopsy is hindered by the lack of methods to enrich GBM tumor-specific sEV in the blood. Our team has developed unique tools and expertise in isolating cell/tissue-specific sEV from biofluids. We have previously reported the isolation of sEV derived from specific brain cells in the blood, characterizing them for diagnosing neurodegeneration and predicting treatment response. In this study, we first isolated total sEV (TE) from the plasma of GBM patients (n = 11). Subsequently, we enriched GBM-specific sEV (sEVGBM) from TE using the astrocyte-specific surface marker glutamate aspartate transporter (GLAST). To achieve this, we utilized biotin-tagged GLAST antibody and streptavidin-coated magnetic beads for sEVGBM isolation. We then extensively characterized the size and concentration (number/ml) of sEVGBM by nanoparticle tracking analyses, while evaluating their purity through nanoflow cytometry for GLAST expression. Furthermore, we confirmed the expression of GBM-specific markers EGFRvIII, EPHB2 and IL-13Rα2 on the surface of sEVGBM (n = 3). Importantly, the expression of these markers was significantly enriched on sEVGBM compared to TE, underscoring the significance of our strategy as a potential liquid biopsy for GBM.
CSIG-31. JAK/STAT PATHWAY CO-OPERATES WITH CIC-FUSIONS TO DRIVE CIC- REARRANGED SARCOMAS
Authors: Ramneet Kaloti, Severa Bunda, Gelareh Zadeh
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND CIC-rearranged sarcoma (CRS) is a rare disease driven by a specific fusion protein involving the CIC gene. The native CIC protein is a transcriptional repressor of the (RTK)/Ras/ERK signaling pathway, which is one of the most tumorigenic pathways in cancer. The most common rearrangement is with the double homeobox 4 (DUX4) transcription factor (CIC-DUX4), and others, such as CIC-NUTM1 fusions, have been identified in a subset of pediatric primitive neuroectodermal tumors. However, the molecular mechanisms by which CIC-fusions drive CRS remain unknown. HYPOTHESIS Preliminary data shows that CIC-DUX4/NUTM1 fusions activate JAK (cytokine receptors) and its downstream effector STAT1/3 (signal transducers and transcription factors). We hypothesize that the JAK/STAT1/3 signal transduction pathway cooperates with CIC-fusions to induce the expression of oncogenic transcription factors ETV1/4/5 and drive these sarcomas. METHODS AND RESULTS JAK1 is a potential target for CIC-fusions - We show high levels of JAK1/STAT1/3 activation in patient-derived CRS cell lines (NCC-SCC-89/C) as compared to other sarcoma cell lines without the fusion. JAK1 inhibition using Solicitinub and Ruxolitinib reduced phosphorylation of STAT1/3 as well as protein and mRNA expression of ETV1/4/5 and cell proliferation. JAK1/STAT1/3 inhibition in patient-derived CIC-DUX4 xenograft models- To evaluate the pre-clinical effect of targeting the JAK1/STAT1/3 pathway, A CRS cell line (NCC-SCC-89/C) were grafted into NSG mice. Ruxolitinib treatment significantly reduced tumor volume, STAT activation, and ETV1/4/5. CONCLUSION We show that the JAK1/STAT1/3 pathway plays a critical role in cooperating with CIC-fusions to drive CRS, providing insight into potential therapeutic avenues for these aggressive tumors.
QOL-13. MEASURING FEAR OF CANCER RECURRENCE IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Sarah Braun, Samantha Mladen, Jenna Langbein, Jacob Verter, Autumn Lanoye, Ashlee Loughan, Sébastien Simard
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Fear of cancer recurrence (FCR) differs for those living with primary brain tumor compared to other cancers due to poorer prognosis, neurologic symptoms, and often lifelong treatment. The gold-standard instrument used to assess FCR–the FCR Inventory (FCRI)–has not been validated in patients with PBT. The present study explored the psychometric properties of the FCRI in patients with brain tumors, with items added assessing brain tumor-specific distress. METHODS Adult patients with brain tumors (n = 87) completed the FCRI and other psychological medical, and demographic questionnaires. Exploratory factor analysis (EFA) was conducted on the FCRI with five additional items informed by neuro-oncology patients and professionals assessing brain tumor-specific hypervigilance (e.g., interpreting headache or cognitive difficulties as possible tumor growth) and one item assessing tendency to research treatments—for a total of 48 items. Correlations investigated convergent/discriminant validity and relationships with relevant medical and demographic variables. RESULTS After iteration, EFA revealed a seven-factor model with 24 retained items, accounting for 68.19% of variance, with factor correlations between .12 and .65. The seven-factor model echoed but did not fully replicate the original FCRI. FCRI-Brain factors were: Triggers, Psychological Distress, Functional Impairments, Insight, Reassurance, Emotion-Focused Coping, and Problem-Focused Coping (Total: Cronbach’s a = .92). The resultant FCRI-Brain demonstrated good convergent validity with measures of depression (r = .57), anxiety (r = .71), and death anxiety (r = .81; ps&amp;lt; .05). Lack of correlation with education (p &amp;gt; .05) supported discriminant validity. There was no relationship with time since diagnosis (p &amp;gt; .05). CONCLUSIONS These data represent the initial validation of an FCR measure in patients with brain tumors. Factor analysis identified a theoretically similar; yet unique seven-factor model for the FCRI-Brain. Item-level exploration will be presented, including further discussion of factor iteration and construction. Future work will build on this data in larger samples and inform intervention development.
DISP-10. ENHANCING TRUST AND REPRESENTATIVE PARTICIPATION IN THE INTERNATIONAL LOW GRADE GLIOMA REGISTRY: COMMUNITY ENGAGEMENT STRATEGIES AND RECOMMENDATIONS
Authors: Liz Salmi, Juliana Barnard, Carly Ritger, Rudy Fischmann, Sandra Garcia-Hernandez, Nestelynn Gay, Ricardo Gonzalez-Fisher, Kevin Johnson, Lindsay Lennox, Guy Lipof, Jasmyn Ostmeyer, Ifeoma Perkins, Jenna Reno, Taylor Roth, Anowara Begum, Elizabeth Claus, Roel Verhaak, Bethany Kwan
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The International Low Grade Glioma (LGG) Registry is a community of people with LGGs who have contributed data and specimens to facilitate genomic research. The Registry aims to discover the roles genetics and the environment play in glioma risk factors and treatment response. To ensure findings apply to a range of diverse populations and settings, it is crucial to build trust and encourage representative participation in the Registry. METHODS Three engagement strategies were used to gather recommendations for improving trust and participation in LGG genomic research. We established a Research Advisory Council (RAC) consisting of 25 members, including people with LGG, care partners, clinicians, researchers, advocates, and genomics and ethics experts. Additionally, we engaged two existing social media communities (the #BTSM community on Twitter, the Oligodendroglioma/LGG Warriors Facebook group) through separate discussions with each group over four months. Topics included: 1) Trust and benefits of genomic research; 2) Registry recruitment; 3) Registry data collection; and 4) Return of results. We used qualitative methods to summarize recommendations. RESULTS Feedback received from community members indicated a willingness to share information with the Registry. Recommendations related to recruitment message content and packaging, communication channels, data security, and conveying the individual- and population-level impacts of genomic research. The Registry’s messages should include clear information about how data and specimens are being used. Both research and individual-level findings should be shared back with participants and the broader community using accessible language, but without being paternalistic or promising cures or “miracles.” CONCLUSIONS Engaging an advisory council and existing social media communities were effective approaches for identifying recommendations for enhancing trust and participation in genomic research. Regular, consistent, transparent communication with participants throughout the research process is key. Future efforts will operationalize and evaluate the impact of these recommendations on equity and representativeness of Registry participants.
EPID-02. HISTORY OF ALLERGY OR ATOPY DECREASES RISK OF BRAIN METASTASIS IN LUNG CANCER AND MELANOMA
Authors: Corey Neff, Mackenzie Price, Zhen Liu, Gino Cioffi, Jill Barnholtz-Sloan, Kyle Walsh, Peter Fecci, Quinn Ostrom
Journal: Neuro-Oncology (2023)

Abstract Both allergy/atopy and autoimmune disease (AD) are associated with decreased prevalence of glioma. We leveraged cancer registry data combined with Medicare claims to investigate the effect of prior atopy/AD on incidence, and overall survival, of brain metastasis (BrM) in lung cancer (LC) and melanoma. Surveillance, Epidemiology and End. RESULTS: data linked to Medicare claims were obtained, containing cases of melanoma and LC diagnosed from 2008-2017. Patients &amp;lt; 65 years of age, enrolled in Medicare Advantage, with prior/subsequent cancer diagnosis, or missing variables were excluded. History of allergy/atopy/ or AD (≥6 months prior to primary cancer diagnosis) and BrM status were identified by ICD-9/ICD-10 codes and SEER variables. Treatment pattern was determined using ICD-9/ICD-10 and HCPCS/CPT codes. Time to BrM and overall survival among individuals diagnosed with BrM were estimated via Cox proportional hazards regression adjusted for age, sex, race/ethnicity, stage at diagnosis, treatment, and Charlson comorbidity score. Of the 154,203 and 66,593 cases of LC and melanoma, 18.6% and 2.5% developed BrM at any point, respectively. Among LC with BrM, 27% and 16% had atopy and/or AD (compared to 33% and 20% in LC without BrM), while there were 26% and 16% of cases with atopy and/or AD among melanoma with BrM (compared to 33% and 18% in melanoma without BrM). History of atopy was associated with decreased hazard of BrM in melanoma and LC (HR=0.73, p-value&amp;lt; 0.001 and HR=0.90, p=0.024, respectively). Among those with a BrM, both history of atopy and AD were associated with improved survival in LC (HR=0.90, p&amp;lt; 0.001 and HR=0.95, p&amp;lt; 0.001) but not melanoma. History of AD is associated with a moderate survival benefit in LC with BrM, while history of allergy/atopy decreased incidence of BrM in LC and melanoma. Further research is necessary to identify potential causes of this association.
BIOM-06. LONGITUDINAL CEREBROSPINAL FLUID LIQUID BIOPSY IN PHASE 0/2 TRIAL OF NIRAPARIB FOR NEWLY-DIAGNOSED GLIOBLASTOMA
Authors: Charuta Furey, Anita DeSantis, Connor White, An-Chi Tien, Shwetal Mehta, Nader Sanai
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Effective drug development in glioblastoma (GBM) requires visualization of tumor evolution in response to experimental therapy. Today, genetic and epigenetic mechanisms of tumor resistance are undetected in clinical trials. Here, we establish the feasibility of a liquid biopsy paradigm in tracking tumor evolution in response to a novel therapeutic using an intra-cavitary reservoir for serial cerebrospinal fluid (CSF) collection. METHODS We conducted a Phase 0/2 clinical trial of niraparib, a potent PARP1/2 inhibitor, in newly-diagnosed GBM patients (NCT05076513). Intra-cavitary reservoirs were placed in select patients following tumor resection. Monthly outpatient CSF samples were collected to longitudinally examine cell-free tumor DNA (cfDNA) using a 293-gene amplicon-based next-generation sequencing (NGS) panel and circulating tumor cells using single cell RNA-sequencing (scRNA-seq). Concordance analysis was performed using paired tumor tissue samples against multiple liquid biopsies. RESULTS Tumor-derived cfDNA and circulating tumor cells were successfully isolated from intra-cavitary reservoirs at regular intervals for the duration of the clinical trial. Twelve patients so far have been implanted with the reservoirs for CSF collection. Among 55 CSF samples, 53 (94%) has detectable cfDNA. Radiographic tumor burden is associated with concentration of cfDNA (ng/ml, p&amp;lt; 0.01). No adverse events were observed during liquid biopsy acquisition. CSF sequencing data was highly concordant with NGS analyses of tumor tissue. cfDNA and single-cell analyses from serial CSF samples reflected the disparate evolution of GBM patient tumors in the face of PARP1/2 inhibition. CONCLUSION This is the first reported experience of serial CSF liquid biopsy to monitor DNA- and RNA-based tumor evolution in the context of an experimental therapy. Our data demonstrate the feasibility of cfDNA NGS and scRNA-seq using longitudinal CSF sampling of clinical trial patients. This new strategy for serial tumor profiling will be an important component of future drug development efforts targeting the moving biology of glioblastoma.